US7183276B2 - Azole compounds - Google Patents

Azole compounds Download PDF

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US7183276B2
US7183276B2 US10/505,742 US50574204A US7183276B2 US 7183276 B2 US7183276 B2 US 7183276B2 US 50574204 A US50574204 A US 50574204A US 7183276 B2 US7183276 B2 US 7183276B2
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group
optionally substituted
alkyl
compound
oxazolyl
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US20050090534A1 (en
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Nozomu Sakai
Yu Momose
Katsuhito Murase
Masatoshi Hazama
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/38—One oxygen atom attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/46—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/40—Unsubstituted amino or imino radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07F9/653—Five-membered rings
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings

Definitions

  • the present invention relates to an azole compound having a promoting action on the production or secretion of a neurotrophic factor and useful for the prophylaxis or treatment of diabetic neuropathy and the like.
  • Azole compounds are described in, for example, the following references.
  • R 1 is a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group
  • A is an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified or amidated carboxyl group
  • B is an optionally substituted aromatic group
  • Y is a divalent aliphatic hydrocarbon group is useful as an agent for the prophylaxis or treatment of diabetes.
  • R 1 is a halogen atom, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group
  • A is an optionally substituted acyl group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group or an optionally esterified or amidated carboxyl group
  • B is an optionally substituted aromatic group
  • X is an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom
  • Y is a divalent hydrocarbon group or heterocyclic group is useful as a neurotrophin production or secretion promoter.
  • R 1 is an aromatic hydrocarbon group or an aromatic heterocyclic group, each of which is optionally substituted;
  • R 2 is a hydrogen or an optionally substituted hydrocarbon group;
  • An object of the present invention is to provide an azole compound having a superior promoting action on the production or secretion of a neurotrophic factor and is of lower toxicity.
  • R 1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted thiol group or an optionally substituted amino group,
  • the present invention relates to
  • halogen atom for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be mentioned. Of these, a fluorine atom and a chlorine atom are preferable.
  • hydrocarbon group in the “optionally substituted hydrocarbon group” for R 1 , for example, an aliphatic hydrocarbon group, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic aliphatic hydrocarbon group, an alicyclic aliphatic hydrocarbon group and the like can be mentioned.
  • aliphatic hydrocarbon group for example, a straight-chain or branched aliphatic hydrocarbon group having 1 to 15 carbon atoms, specifically an alkyl group, an alkenyl group, an alkynyl group and the like can be mentioned.
  • alkyl group C 1-10 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like can be mentioned.
  • C 1-10 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohe
  • alkenyl group C 2-10 alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be mentioned.
  • alkynyl groups C 2-10 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like can be mentioned.
  • alicyclic hydrocarbon group for example, a saturated or unsaturated alicyclic hydrocarbon group having 3 to 12 carbon atoms, specifically a cycloalkyl group, a cycloalkenyl group, a cycloalkadienyl group and the like, can be mentioned.
  • C 3-10 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl and the like can be mentioned.
  • C 3-10 cycloalkenyl groups such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like can be mentioned.
  • cycloalkadienyl group C 4-10 cycloalkadienyl groups such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like can be mentioned.
  • aromatic hydrocarbon group for example, a C 6-14 aryl group and the like can be mentioned.
  • aryl group phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl, indenyl and the like can be mentioned. Of these, phenyl, naphthyl and the like are preferable.
  • the aryl group may be partially saturated and as the partially saturated aryl group, for example, dihydroindenyl, tetrahydronaphthyl and the like can be mentioned.
  • aromatic aliphatic hydrocarbon group for example, a C 7-14 aromatic aliphatic hydrocarbon group, and concretely, an aralkyl group, an arylalkenyl group, an arylalkynyl group and the like can be mentioned.
  • C 7-14 aralkyl groups such as benzyl, phenethyl, naphthylmethyl, benzhydryl, phenylpropyl, phenylbutyl, diphenylethyl and the like can be mentioned.
  • arylalkenyl group C 8-13 arylalkenyl groups such as styryl and the like can be mentioned.
  • arylalkynyl group C 8-13 arylalkynyl groups such as phenylethynyl and the like can be mentioned.
  • alicyclic aliphatic hydrocarbon group for example, a C 4-13 alicyclic aliphatic hydrocarbon group, and concretely, a cycloalkylalkyl group, a cycloalkylalkenyl group, a cycloalkenylalkyl group and the like can be mentioned.
  • cycloalkylalkyl group C 4-13 cycloalkylalkyl groups such as cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and the like can be mentioned.
  • cycloalkylalkenyl group C 5-13 cycloalkylalkenyl groups such as cyclopropylethenyl, cyclopentylethenyl, cyclohexylethenyl and the like can be mentioned.
  • cycloalkenylalkyl group C 4-13 cycloalkenylalkyl groups such as cyclopentenylmethyl, cyclopentenylethyl, cyclohexenylmethyl, cyclohexenylethyl and the like can be mentioned.
  • the above-mentioned “optionally substituted hydrocarbon group” for R 1 may have 1 to 3 substituent(s) at substitutable position(s).
  • substituent for example, a halogen atom, a nitro, an oxo, a C 1-3 alkylenedioxy, an optionally substituted aromatic heterocyclic group, an optionally substituted non-aromatic heterocyclic group, an optionally substituted amino group, an optionally substituted hydroxy group, an optionally substituted thiol group, an optionally substituted acyl group and the like can be mentioned.
  • halogen atoms for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be mentioned. Especially preferred are a fluorine atom and a chlorine atom.
  • C 1-3 alkylenedioxy for example, methylenedioxy, ethylenedioxy and the like can be mentioned.
  • aromatic heterocyclic group of the “optionally substituted aromatic heterocyclic group”, for example, a 5- to 7-membered monocyclic aromatic heterocyclic group which contains, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a condensed aromatic heterocyclic group can be mentioned.
  • condensed aromatic heterocyclic group for example, a group wherein the 5- to 7-membered monocyclic aromatic heterocyclic group is condensed with a 6-membered ring containing 1 or 2 nitrogen atom(s), a benzene ring, a 5-membered ring containing 1 sulfur atom, and the like can be mentioned.
  • furyl e.g., 2-furyl, 3-furyl
  • thienyl e.g., 2-thienyl, 3-thienyl
  • pyridyl e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl
  • pyridazinyl e.g., 3-pyridazinyl, 4-pyridazinyl
  • pyrazinyl e.g., 2-pyrazinyl
  • pyrrolyl e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl
  • pyrazolyl e.g., 1-imi
  • non-aromatic heterocyclic group of the “optionally substituted non-aromatic heterocyclic group”, for example, a 5- to 7-membered monocyclic non-aromatic heterocyclic group which contains, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a condensed non-aromatic heterocyclic group can be mentioned.
  • condensed non-aromatic heterocyclic group for example, a group wherein the 5- to 7-membered monocyclic non-aromatic heterocyclic group is condensed with a 6-membered ring containing 1 or 2 nitrogen atom(s), a benzene ring, a 5-membered ring containing 1 sulfur atom, and the like can be mentioned.
  • non-aromatic heterocyclic group pyrrolidinyl (e.g., 1-pyrrolidinyl), piperidinyl (e.g., piperidino), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino), piperazinyl (e.g., 1-piperazinyl), hexamethyleniminyl (e.g., hexamethylenimin-1-yl), oxazolidinyl (e.g., oxazolidin-3-yl), thiazolidinyl (e.g., thiazolidin-3-yl), imidazolidinyl (e.g., imidazolidin-3-yl), imidazolinyl (e.g., imidazolin-1-yl, imidazolin-2-yl), oxazolinyl (e.g.,
  • the above-mentioned aromatic heterocyclic group and non-aromatic heterocyclic group may have 1 to 3 substituent(s) at substitutable position(s).
  • substituent for example, a nitro, a hydroxy, an amino, an oxo, a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a C 1-6 alkyl (e.g., methyl, ethyl) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), a C 1-6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), a C 6-14 aryl (e.g., phenyl) and the like can be mentioned.
  • an amino group optionally mono- or di-substituted by a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, a C 7-14 aralkyl, a C 1-15 acyl group or a heteroaryl group, each of which is optionally substituted can be mentioned.
  • C 1-10 alkyl group C 2-10 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aryl group and C 7-14 aralkyl
  • hydrocarbon group of the “optionally substituted hydrocarbon group” for R 1
  • the acyl group is preferably a formyl, a C 1-10 alkyl-carbonyl, a C 1-6 alkoxy-carbonyl, a C 6-14 aryl-carbonyl, a C 7-13 aralkyl-carbonyl, an aromatic heterocyclic-carbonyl, a 5- to 7-membered non-aromatic heterocyclic-carbonyl, a C 3-10 cycloalkyl-carbonyl (e.g., cyclopentanecarbonyl, cyclohexanecarbonyl); a C 8-13 arylalkenyl-carbonyl (e.g., styrylcarbonyl); a C 8-13 arylalkynyl-carbonyl (e.g., phenylethynylcarbonyl); a C 6
  • a C 1-6 alkoxy-carbamoyl e.g., methoxycarbamoyl
  • a C 1-6 alkoxy-carbonylcarbamoyl e.g., methoxycarbonylcarbamoyl, ethoxycarbonylcarbamoyl
  • the like can be also mentioned.
  • C 1-10 alkyl-carbonyl acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl and the like can be mentioned.
  • C 1-6 alkoxy-carbonyl for example, tert-butoxycarbonyl and the like can be mentioned.
  • aromatic heterocyclic-carbonyl furylcarbonyl, pyrrolylcarbonyl, thienylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, 1H-indazolylcarbonyl, benzofuranylcarbonyl, quinolylcarbonyl and the like can be mentioned.
  • heteroaryl group for example, the aromatic heterocyclic groups exemplified for the substituents of the “optionally substituted heterocyclic group” for R 1 can be mentioned.
  • pyridyl, imidazolyl, triazolyl, pyrimidinyl and the like are preferable.
  • the C 1-10 alkyl group, C 2-10 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aryl group, C 7-14 aralkyl, C 1-15 acyl group and heteroaryl group may have 1 or 2 substituent(s) at substitutable position(s).
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkyl group e.g., methyl, trifluoromethyl
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkoxy group e.g., methoxy, ethoxy
  • halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkyl group e.g., methyl, trifluoromethyl
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkoxy group e.g., methoxy, ethoxy
  • halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a hydroxy; a nitro; an amino; a C 1-6 alkylsulfonyl group e.g., methylsulfonyl
  • the like are preferable.
  • a mono- or di-C 1-10 alkylamino e.g., methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino, propylamino, dibutylamino
  • a mono- or di-C 2-10 alkenylamino e.g., diallylamino
  • a mono- or di-C 3-10 cycloalkylamino e.g., cyclohexylamino
  • a mono- or di-C 1-10 alkyl-carboxamide e.g., acetylamino, propionylamino
  • 1 to 3 substituent(s) selected from a heterocyclic thio optionally substituted C 1-6 alkyl (e.g., pyrimidinylthio), C 6-14 ary
  • a hydroxy group optionally substituted by a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, a C 7-14 aralkyl, a C 1-15 acyl group or a heteroaryl group, each of which is optionally substituted can be mentioned.
  • C 1-10 alkyl group C 2-10 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aryl group and C 7-14 aralkyl
  • hydrocarbon group of the “optionally substituted hydrocarbon group” for R 1
  • heteroaryl group for example, aromatic heterocyclic groups exemplified for the substituents of the “optionally substituted heterocyclic group” for R 1 can be mentioned.
  • pyridyl, imidazolyl, triazolyl, pyrimidinyl and the like are preferable.
  • C 1-10 alkyl group may have 1 or 2 substituent(s) at substitutable position(s).
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkyl group e.g., methyl, trifluoromethyl
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkoxy group e.g., methoxy, ethoxy
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a hydroxy, a nitro, an amino, a C 1-6 alkylsulfonyl group e.g., methylsulfonyl
  • substituted hydroxy group for example, an alkoxy group, an alkenyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, an aryloxy group, an aralkyloxy group, an acyloxy group, a heteroaryloxy group, each of which is optionally substituted and the like, can be mentioned.
  • a C 1-10 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, nonyloxy and the like, can be mentioned.
  • alkenyloxy group a C 2-10 alkenyloxy group, such as allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy and the like, can be mentioned.
  • cycloalkyloxy group a C 3-10 cycloalkyloxy group, such as cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, can be mentioned.
  • C 3-10 cycloalkenyloxy group such as 2-cyclopentenyloxy, 2-cyclohexenyloxy and the like, can be mentioned.
  • aryloxy group a C 6-14 aryloxy group, such as phenoxy, naphthyloxy and the like, can be mentioned.
  • a C 7-14 aralkyloxy group such as benzyloxy, phenethyloxy, naphthylmethyloxy and the like, can be mentioned.
  • acyloxy group a C 2-13 acyloxy group, such as C 1-6 alkyl-carbonyloxy (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy) and the like, can be mentioned.
  • C 1-6 alkyl-carbonyloxy e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy
  • heteroaryloxy group a 5- to 7-membered monocyclic heteroaryloxy group, such as 2-pyridyloxy, 3-pyridyloxy, 2-imidazolyloxy, 2-pyrimidinyloxy, 1,2,4-triazol-5-yloxy and the like, can be mentioned.
  • alkoxy group, alkenyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, aralkyloxy group, acyloxy group and heteroaryloxy group may have 1 or 2 substituent(s) at substitutable position(s).
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkyl group e.g., methyl, trifluoromethyl
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkoxy group e.g., methoxy, ethoxy
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a hydroxy, a nitro, an amino, a C 1-6 alkylsulfonyl group e.g., methylsulfonyl
  • thiol group for example, a thiol group optionally substituted by “C 1-10 alkyl group”, “C 2-10 alkenyl group”, “C 3-10 cycloalkyl group”, “C 3-10 cycloalkenyl group”, “C 6-14 aryl group”, “C 7-14 aralkyl”, “C 1-15 acyl group” or “heteroaryl group”, each of which is optionally substituted, and the like can be mentioned.
  • C 1-10 alkyl group “C 2-10 alkenyl group”, “C 3-10 cycloalkyl group”, “C 3-10 cycloalkenyl group”, “C 6-14 aryl group”, “C 7-14 aralkyl”, “C 1-15 acyl group” and “heteroaryl group”, those respectively exemplified for the aforementioned “optionally substituted hydroxy group” can be mentioned.
  • These groups may have 1 or 2 substituent(s) at substitutable position(s).
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkyl group e.g., methyl, trifluoromethyl
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkoxy group e.g., methoxy, ethoxy
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a hydroxy, a nitro, an amino, a C 1-6 alkylsulfonyl group e.g., methylsulfonyl
  • an oxo a pyridyl and the like
  • substituted thiol group for example, an alkylthio, an alkenylthio, a cycloalkylthio, a cycloalkenylthio, an arylthio, an aralkylthio, an acylthio, a heteroarylthio, each of which is optionally substituted, and the like, can be mentioned.
  • alkylthio group a C 1-10 alkylthio group, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio and the like, can be mentioned.
  • a C 1-10 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, nonylthio and
  • alkenylthio group a C 2-10 alkenylthio group, such as allylthio, crotylthio, 2-pentenylthio, 3-hexenylthio and the like can be mentioned.
  • cycloalkylthio group a C 3-10 cycloalkylthio group, such as cyclobutylthio, cyclopentylthio, cyclohexylthio and the like, can be mentioned.
  • cycloalkenylthio group a C 3-10 cycloalkenylthio group, such as 2-cyclopentenylthio, 2-cyclohexenylthio and the like, can be mentioned.
  • arylthio group a C 6-14 arylthio group, such as phenylthio, naphthylthio and the like, can be mentioned.
  • aralkylthio group a C 7-14 aralkylthio group, such as benzylthio, phenethylthio, naphthylmethylthio and the like, can be mentioned.
  • acylthio group a C 2-13 acylthio group, such as a C 1-6 alkyl-carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio), and the like can be mentioned.
  • a C 1-6 alkyl-carbonylthio group e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio
  • heteroarylthio group a 5- to 7-membered monocyclic heteroarylthio group, such as 2-pyridylthio, 3-pyridylthio, 2-imidazolylthio, 2-pyrimidinylthio, 1,2,4-triazol-5-ylthio, 1,2,4-triazol-3-ylthio and the like, can be mentioned.
  • alkylthio group alkenylthio group, cycloalkylthio group, cycloalkenylthio group, arylthio group, aralkylthio group, acylthio group and heteroarylthio group may have 1 or 2 substituent(s) at substitutable position(s).
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkyl e.g., methyl, trifluoromethyl
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a C 1-6 alkoxy e.g., methoxy, ethoxy
  • 1 to 3 halogen atom(s) e.g., fluorine, chlorine, bromine, iodine
  • a hydroxy, a nitro, an amino, a C 1-6 alkylsulfonyl e.g., methylsulfonyl
  • an oxo pyridyl and the like
  • acyl group of the “optionally substituted acyl group” for example, a group represented by the formula: —COR 3 , —CO—OR , —SO 2 R 3 , —SOR 3 , —PO 3 R 3 R 4 , —CO—NR 3a R 4a , —CS—NR 3a R 4a wherein R 3 and R 4 are the same or different and each is a hydrogen atom, a hydrocarbon group or a heterocyclic group, or R 3 and R 4 may form a heterocycle together with the adjacent oxo-substituted phosphorus atom and 2 oxygen atoms; R 3a and R 4a are the same or different and each is a hydrogen atom, a hydrocarbon group or a heterocyclic group, or R 4a and R 5a may form a nitrogen-containing heterocycle together with the adjacent nitrogen atom, and the like can be mentioned.
  • the hydrocarbon group is preferably a C 1-10 alkyl group (preferably methyl, ethyl, propyl, butyl, tert-butyl, pentyl, 1-ethylpropyl, 2,2-dimethylpropyl, isopentyl, hexyl); a C 2-10 alkenyl group (preferably 1-propenyl); a C 2-10 alkynyl group (preferably 2-propynyl); a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl) which may be condensed with a benzene ring; a C 3-10 cycloalkenyl group (preferably 2-cyclohexenyl); a C 6-14 aryl group (preferably phenyl, dihydroindenyl, biphenylyl) which may be condensed with a C 3-10 cycloalkane (
  • heterocyclic group for R 3 , R 4 , R 3a or R 4a
  • aromatic heterocyclic group and the non-aromatic heterocyclic group exemplified for the substituents of the “optionally substituted hydrocarbon group” for R 1 can be mentioned.
  • the heterocyclic group is preferably thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, pyrrolidinyl, piperidinyl, piperazinyl, furyl, thienyl, pyrimidinyl, benzofuryl, 1H-indazolyl, morpholinyl, thiomorpholinyl, hexamethyleniminyl, tetrahydroisoquinolyl, oxazolidinyl, thiazolidinyl and the like.
  • heterocycle formed by R 3 and R 4 together with the adjacent oxo-substituted phosphorus atom and 2 oxygen atoms for example, a 4- to 7-membered heterocycle containing an oxo-substituted phosphorus atom and 2 oxygen atoms besides carbon atoms as a ring-constituting atom, which may further contain 1 or 2 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the like can be mentioned.
  • 2-oxide-1,3,2-dioxaphosphinane; 2-oxide-1,3,2-dioxaphosphorane and the like can be mentioned.
  • nitrogen-containing heterocycle formed by R 3a and R 4a together with the adjacent nitrogen atom
  • a 5- to 7-membered nitrogen-containing heterocycle containing at least one nitrogen atom besides carbon atoms as a ring-constituting atom, which may further contain 1 or 2 heteroatom(s) selected from an oxygen atom, a sulfur atom and a nitrogen atom, and the like can be mentioned.
  • pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine and the like can be mentioned.
  • acyl group examples include formyl; carboxyl; carbamoyl; thiocarbamoyl; C 1-10 alkyl-carbonyl (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoly); C 2-10 alkenyl-carbonyl (e.g., crotonyl); C 3-10 cycloalkyl-carbonyl (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl); C 3-10 cycloalkenyl-carbonyl (e.g., 2-cyclohexenecarbonyl); C 6-14 aryl-carbonyl (e.g., benzoyl, 1-naphthyl, ace
  • the acyl group may have 1 to 3 substituent(s) at substitutable position(s).
  • substituent for example, a C 1-6 alkyl (e.g., methyl, ethyl) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine); a C 1-6 alkoxy (e.g., methoxy, ethoxy) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine); a halogen atom (e.g., fluorine, chlorine, bromine, iodine); a nitro; a hydroxy; an amino optionally mono- or di-substituted by C 1-6 alkyl (e.g., methyl, ethyl); a cyano; a mono- or di-C 1-10 alkylphosphono-C 1-6 alkyl group (
  • acyl group formyl; carboxyl; carbamoyl; thiocarbamoyl; C 1-10 alkyl-carbonyl (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoly); C 2-10 alkenyl-carbonyl (e.g., crotonyl); C 3-10 cycloalkyl-carbonyl (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl); C 3-10 cycloalkenyl-carbonyl (e.g., 2-cyclohexenecarbonyl); C 6-14 aryl-carbonyl (e.g., benzoyl, 1-naphtho
  • C 1-6 alkoxy-carbamoyl e.g., methoxycarbamoyl
  • C 1-6 alkoxy-carbonylcarbamoyl e.g., methoxycarbonylcarbamoyl, ethoxycarbonylcarbamoyl
  • C 7-14 aralkyloxy-carbamoyl e.g., benzyloxycarbamoyl
  • the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1 is preferably a C 1-10 alkyl group, a C 6-14 aryl group, a C 3-10 cycloalkyl group, a C 7-14 aralkyl group, a C 8-13 arylalkenyl group, a C 4-13 cycloalkylalkyl group and the like.
  • the hydrocarbon group is more preferably a C 6-14 aryl group, and phenyl, naphthyl and the like are particularly preferable.
  • the substituent of the “optionally substituted hydrocarbon group” for R 1 is preferably a C 1-6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a nitro, a hydroxy, an amino, a C 1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy) and the like.
  • the number of the substituent is, for example, 1 to 3.
  • heterocyclic group of the “optionally substituted heterocyclic group” for R 1 , those exemplified for the aforementioned “heterocyclic group” for the aforementioned R 3 can be mentioned.
  • the heterocyclic group is preferably an azolyl group optionally condensed with a benzene ring, such as pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and the like.
  • a benzene ring such as pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, and the like.
  • imidazolyl, benzimidazolyl, indolyl, 1H-indazolyl and the like are preferable, and imidazolyl, benzimidazolyl and the like are particularly preferable.
  • the heterocyclic group for R 1 may have 1 to 3 substituent(s) at substitutable position(s).
  • substituent for example, an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic heterocyclic group, an optionally substituted non-aromatic heterocyclic group, a halogen atom, a nitro, an optionally substituted amino group, an optionally substituted acyl group, optionally substituted hydroxy group, an optionally substituted thiol group, an optionally substituted acyl group, a C 1-3 alkylenedioxy, an oxo and the like can be mentioned.
  • aliphatic hydrocarbon group “alicyclic hydrocarbon group” and “aromatic hydrocarbon group” of the “optionally substituted aliphatic hydrocarbon group”, “optionally substituted alicyclic hydrocarbon group” and “optionally substituted aromatic hydrocarbon group”, those exemplified for the “hydrocarbon group” of the “optionally substituted hydrocarbon group” for R 1 can be mentioned.
  • aromatic heterocyclic group and “non-aromatic heterocyclic group” of the “optionally substituted aromatic heterocyclic group” and “optionally substituted non-aromatic heterocyclic group”, those exemplified for the substituent of the “optionally substituted hydrocarbon group” for R 1 can be mentioned.
  • the substituent of the “optionally substituted heterocyclic group” for R 1 preferably includes a C 1-6 alkyl (e.g., methyl, ethyl) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), a C 1-6 alkoxy (e.g., methoxy, ethoxy) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a nitro, a hydroxy, an amino, a C 6-14 aryl (e.g., phenyl), a C 1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy), a C 1-10 alkylsulfonyl group (e.g., methyls
  • R 1 is preferably an “optionally substituted heterocyclic group”.
  • the heterocyclic group is preferably an azolyl group optionally condensed with a benzene ring (e.g., pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl), and the like.
  • imidazolyl, benzimidazolyl, indolyl, 1H-indazolyl and the like are preferable, and imidazolyl, benzimidazolyl and the like are particularly preferable.
  • R 1 is more preferably an “azolyl group optionally condensed with a benzene ring (e.g., pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl)” which is optionally substituted by 1 to 3 substituent(s) selected from a C 1-6 alkyl (e.g., methyl, ethyl) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), a C 1-6 alkoxy (e.g., methoxy, ethoxy) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), a halogen atom (e.g
  • imidazolyl and benzimidazolyl each of which is optionally substituted by C 1-6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), are preferable.
  • R 1 is particularly preferably benzimidazolyl.
  • A is an “optionally substituted cyclic amino group” or “—NR 2 —W—D (R 2 is a hydrogen atom or an alkyl group, W is a bond or a divalent acyclic hydrocarbon group, and D is an optionally substituted cyclic group, an optionally substituted amino group or an optionally substituted acyl group)”.
  • cyclic amino group of the “optionally substituted cyclic amino group”, for example, a 5- to 8-membered nitrogen-containing heterocyclic group containing at least one nitrogen atom besides carbon atoms as ring-constituting atoms and optionally further containing 1 or 2 heteroatom(s) selected from an oxygen atom, a sulfur atom and a nitrogen atom can be mentioned.
  • nitrogen-containing heterocyclic group examples include 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-azepanyl, 1-azocanyl, 3-thiazolidinyl, 3-oxazolidinyl and the like.
  • 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl and the like are preferable.
  • the “cyclic amino group” optionally has 1 to 3 substituent(s) at substitutable position(s).
  • substituent for example, 1,
  • the “optionally substituted cyclic amino group” for A is preferably 1-piperidinyl, 1-piperazinyl, 4-morpholinyl or 4-thiomorpholinyl, each optionally having 1 to 3 substituent(s) selected from
  • R 2 for example, a C 1-6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl) can be mentioned. Particularly, methyl is preferable.
  • R 2 is preferably a hydrogen atom.
  • the “divalent acyclic hydrocarbon group” for W may be straight-chain or branched and saturated or unsaturated, as long as it is an acyclic divalent hydrocarbon group.
  • a “divalent acyclic hydrocarbon group” for example, a “divalent aliphatic hydrocarbon group” can be mentioned. Particularly, a divalent C 1-8 aliphatic hydrocarbon group is preferable.
  • divalent acyclic hydrocarbon group examples include:
  • the “divalent acyclic hydrocarbon group” is preferably a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, and is more preferably a C 1-4 alkylene. Particularly, —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 — and the like are preferable, and specifically, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 — and the like are preferable.
  • W is preferably a bond or a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms and is more preferably a bond or a C 1-4 alkylene.
  • a bond, —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 — and the like are preferable, and specifically, a bond, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 — and the like are preferable.
  • cyclic group of the “optionally substituted cyclic group” for D is, for example, an alicyclic hydrocarbon group, an aromatic hydrocarbon group, an aromatic heterocyclic group, a non-aromatic heterocyclic group and the like can be mentioned.
  • aromatic heterocyclic group and “non-aromatic heterocyclic group”, those exemplified for the substituents of the “optionally substituted hydrocarbon group” for R 1 can be mentioned.
  • the cyclic group is preferably a C 6-14 aryl group (preferably phenyl, biphenylyl), a C 3-10 cycloalkyl group (preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), a C 3-10 cycloalkenyl group (preferably cyclohexenyl), a 5- or 6-membered aromatic heterocyclic group optionally condensed with a benzene ring (preferably furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, indolyl, quinolyl, isoquinolyl, benzothiazolyl, benzothiadiazolyl, isoxazolyl), a 5- or 6-membered non-aromatic heterocyclic group optionally condensed with a benzene ring
  • the “cyclic group” for D may have 1 to 3 substituent(s) at the substitutable position(s).
  • substituent for example,
  • D is preferably an optionally substituted cyclic group, and more preferably “a C 6-14 aryl group (preferably phenyl, biphenylyl)”, “a 5- or 6-membered aromatic heterocyclic group optionally condensed with a benzene ring (preferably furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, indolyl, quinolyl, isoquinolyl, benzothiazolyl, benzothiadiazolyl, isoxazolyl)” or “a 5- or 6-membered non-aromatic heterocyclic group optionally condensed with a benzene ring (preferably pyrrolidinyl, tetrahydrofuranyl, thiazolinyl, oxazolinyl, thiazolidinyl, oxazolidinyl, dioxolanyl, piperidinyl, piperazin
  • D is particularly preferably a C 6-14 aryl group (preferably phenyl) optionally substituted by C 1-6 alkyl group (preferably methyl, ethyl) optionally substituted by (mono- or di-C 1-10 alkyl)phosphono group optionally forming a ring (preferably dimethylphosphono; diethylphosphono; diisopropylphosphono; dibutylphosphono; 2-oxide-1,3,2-dioxaphosphinanyl).
  • C 6-14 aryl group preferably phenyl
  • C 1-6 alkyl group preferably methyl, ethyl
  • (mono- or di-C 1-10 alkyl)phosphono group optionally forming a ring (preferably dimethylphosphono; diethylphosphono; diisopropylphosphono; dibutylphosphono; 2-oxide-1,3,2-dioxaphosphinanyl).
  • B is preferably an “optionally substituted hydrocarbon group”, and is more preferably a C 1-10 alkyl group (e.g., methyl, isopropyl, t-butyl) or an optionally substituted C 6-14 aryl group. Particularly, an optionally substituted C 6-14 aryl group is preferable.
  • B include a C 6-14 aryl group (preferably phenyl or biphenylyl, more preferably phenyl) optionally substituted by 1 to 3 substituent(s) selected from a C 1-6 alkyl (e.g., methyl, ethyl, trifluoromethyl) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), a C 1-6 alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy) optionally substituted by 1 to 3 halogen atom(s) (e.g., fluorine, chlorine, bromine, iodine), a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a nitro, a formyl, a C 1-3 alkylenedioxy (e.g., methylenedioxy) and an aromatic heterocyclic group (
  • a C 6-14 aryl group (preferably phenyl) optionally substituted by 1 to 3 halogen atom(s) (e.g., chlorine, bromine) is preferable.
  • halogen atom(s) e.g., chlorine, bromine
  • X is an oxygen atom, a sulfur atom or an optionally substituted nitrogen atom.
  • optionally substituted nitrogen atom for X for example, —NR 5 — wherein R5 is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group, and the like can be mentioned.
  • R 5 is preferably a hydrogen atom, an optionally substituted hydrocarbon group and the like, more preferably a hydrogen atom, an optionally substituted alkyl group and the like, and particularly, a hydrogen atom, a C 1-4 alkyl group and the like are preferable.
  • X is preferably an oxygen atom or a sulfur atom, more preferably an oxygen atom.
  • Y is preferably a divalent acyclic hydrocarbon group, more preferably a divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, particularly preferably a C 1-4 alkylene (preferably —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —).
  • —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 — and the like are preferable, particularly, —(CH 2 ) 2 — and the like are preferable.
  • salts of a compound represented by the formula (I) pharmacologically acceptable salts are preferable.
  • a salt with an inorganic base a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid and a salt with a basic or acidic amino acid can be mentioned.
  • the salt with an inorganic base include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt and the like; and aluminum salt, ammonium salt and the like.
  • salt with an organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine, and the like.
  • the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid and the like.
  • the salt with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • salt with a basic amino acid examples include salts with arginine, lysine and ornithine and the like.
  • salt with an acidic amino acid examples include salts with aspartic acid, glutamic acid, and the like.
  • a sodium salt a potassium salt, hydrochloride and the like are preferred.
  • a prodrug of the compound (I) means a compound capable of being converted to the compound (I) in vivo by the reaction of an enzyme or gastric juice and the like under physiological conditions, namely a compound capable of being converted to the compound (I) upon enzymatic oxidation, reduction or hydrolysis and the like, or a compound capable of being converted to the compound (I) upon hydrolysis and the like by gastric juice and the like.
  • the prodrug of the compound (I) compounds derived by acylation, alkylation or phosphorylation of the amino group of the compound (I) (e.g.
  • the prodrug of the compound (I) may be one capable of being converted to the compound (I) under physiological conditions, as described in “Iyakuhin no Kaihatsu (Development of Drugs)”, vol. 7, Molecular Designing, published by Hirokawa Shoten, 1990, pages 163–198.
  • the compound (I) may be labeled with an isotope (e.g., 3 H, 14 C, 35 S, 125 I, and the like) and the like.
  • an isotope e.g., 3 H, 14 C, 35 S, 125 I, and the like
  • the compound (I) may be an anhydride or a hydrate.
  • the compound (I) and a prodrug thereof are of lower toxicity and can be used for mammals (e.g. human, mouse, rat, rabbit, dog, cat, cattle, horse, swine, monkey and the like), as an agent for promoting production or secretion of a neurotrophic factor and the like, either as such or by admixing with a pharmacologically acceptable carrier or the like to give a pharmaceutical composition.
  • mammals e.g. human, mouse, rat, rabbit, dog, cat, cattle, horse, swine, monkey and the like
  • a pharmacologically acceptable carrier or the like to give a pharmaceutical composition.
  • various organic or inorganic carrier substances which are conventionally used as pharmaceutical preparation materials can be mentioned. They are incorporated as excipients, lubricants, binders, disintegrants or the like in solid preparations; as solvents, solubilizers, suspending agents, isotonizing agents, buffers, soothing agents or the like in liquid preparations. Where necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners and the like may be used.
  • lactose lactose
  • sucrose D-mannitol
  • D-sorbitol starch
  • pre-gelatinized starch dextrin
  • crystalline cellulose low-substituted hydroxypropylcellulose
  • carboxymethylcellulose sodium acacia
  • dextrin pullulan
  • light silicic anhydride synthetic aluminum silicate
  • magnesium aluminometasilicate magnesium aluminometasilicate and the like
  • magnesium stearate magnesium stearate, calcium stearate, talc, colloidal silica and the like can be mentioned.
  • binders pre-gelatinized starch, sucrose, gelatin, acacia, methylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, crystalline cellulose, saccharose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like can be mentioned.
  • disintegrants lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, light silicic anhydride, low-substituted hydroxypropylcellulose and the like can be mentioned.
  • solvents water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cotton seed oil and the like can be mentioned.
  • solubilizers polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate and the like can be mentioned.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; polysorbates, polyoxyethylene-hardened castor oil, and the like can be mentioned.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like
  • hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethyl
  • sodium chloride sodium chloride, glycerol, D-mannitol, D-sorbitol, glucose and the like can be mentioned.
  • buffer solutions of phosphate, acetate, carbonate, citrate and the like can be mentioned.
  • the soothing agents benzyl alcohol and the like can be mentioned.
  • para-oxybenzoates chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like can be mentioned.
  • antioxidants sulfites, ascorbates and the like can be mentioned.
  • water-soluble edible tar dyes e.g. food colors such as Food Color Red No. 2 and No. 3, Food Color Yellow No. 4 and No. 5, Food Color Blue No. 1 and No. 2
  • water-insoluble lake colors e.g. the aluminum salt of the above water-soluble edible tar dyes and the like
  • natural colors e.g. ⁇ -carotene, chlorophyll, red iron oxide and the like
  • saccharin sodium dipotassium glycyrrhizinate, aspartame, stevia and the like can be mentioned.
  • oral preparations such as tablets (including sublingual tablet and intraorally disintegrating tablet), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, suspensions and the like; or parenteral preparations such as injections (e.g. subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip infusions and the like), external preparations (e.g. transdermal preparations, ointments and the like), suppositories (e.g.
  • rectal suppositories vaginal suppositories and the like
  • pellets transnasal agents
  • transpulmonary agents inhalant
  • eye drops etc., and the like
  • compositions may be controlled-release preparations (e.g., sustained-release microcapsules and the like) such as rapid release preparations, sustained-release preparations and the like.
  • the pharmaceutical composition can be produced by the methods well established in fields of the pharmaceutical manufacturing techniques, for example, by the methods described in the Japanese Pharmacopoeia and the like. In the following, some concrete methods for producing such preparations are described in detail.
  • the content of the compound of the invention in a pharmaceutical composition varies depending on the dosage form, dose of the compound of the invention and the like, but it is, for example, about 0.1–100 wt %.
  • an oral preparation can be produced by adding an excipient (e.g., lactose, sucrose, starch, D-mannitol and the like), a disintegrant (e.g., carboxymethylcellulose calcium and the like), a binder (e.g., pre-gelatinized starch, acacia, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and the like), a lubricant (e.g., talc, magnesium stearate, polyethylene glycol 6000 and the like) and the like to the active ingredient and compression-molding the mixture, and then, if desirable, by coating the molded product by a method known per se with a coating base for the purpose of masking of taste, or imparting enteric property or durability.
  • an excipient e.g., lactose, sucrose, starch, D-mannitol and the like
  • a disintegrant e.g., carboxymethylcellulose calcium and the like
  • the coating base for example, a sugar coating base, a water-soluble film coating base, an enteric film coating base, a sustained-release film coating base and the like can be mentioned.
  • sucrose is used and, further, one or more kinds of ingredients selected from talc, precipitated calcium carbonate, gelatin, acacia, pullulan, carnauba wax and the like may be used in combination.
  • water-soluble film coating base for example, cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like; synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trademark), Roehm Pharma], polyvinylpyrrolidone and the like; polysaccharides such as pullulan and the like, and the like can be mentioned.
  • cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose and the like
  • synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trademark), Roehm Pharma], polyvinylpyrrolidone and the like
  • polysaccharides such as pullulan and the like, and the
  • enteric film coating base for example, cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trademark), Roehm Pharma], methacrylic acid copolymer LD [Eudragit L-30D55 (trademark), Roehm Pharma], methacrylic acid copolymer S [Eudragit S (trademark), Roehm Pharma] and the like; natural products such as shellac and the like, and the like can be mentioned.
  • cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate and the like
  • acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trademark), Roehm Pharma
  • sustained-release film coating base for example, cellulose polymers such as ethylcellulose and the like; acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trademark), Roehm Pharma], an ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trademark), Roehm Pharma] and the like; and the like can be mentioned.
  • cellulose polymers such as ethylcellulose and the like
  • acrylic acid polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trademark), Roehm Pharma], an ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trademark), Roehm Pharma] and the like; and the like can be mentioned.
  • Two or more of the above coating bases may be used in admixture in appropriate proportions.
  • a shading agent such as titanium oxide, ferric oxide and the like may be used.
  • Injections are produced by dissolving, suspending or emulsifying the active ingredient in an aqueous solvent (e.g. distilled water, physiological saline, Ringer's solution) or an oleaginous solvent (e.g. vegetable oils such as olive oil, sesame oil, cotton seed oil, corn oil and the like; propylene glycol and the like), together with dispersants (e.g. polysorbate 80, polyoxyethylene-hardened castor oil 60, polyethylene glycol, carboxymethylcellulose, sodium alginate and the like), preservatives (e.g. methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol and the like), isotonizing agents (e.g.
  • an aqueous solvent e.g. distilled water, physiological saline, Ringer's solution
  • an oleaginous solvent e.g. vegetable oils such as olive oil, sesame oil, cotton seed oil, corn oil and the like; prop
  • additives such as solubilizers (e.g. sodium salicylate, sodium acetate and the like), stabilizers (e.g. human serum albumin and the like), soothing agents (e.g. benzyl alcohol and the like) and the like, may be used.
  • solubilizers e.g. sodium salicylate, sodium acetate and the like
  • stabilizers e.g. human serum albumin and the like
  • soothing agents e.g. benzyl alcohol and the like
  • the compound of the present invention has superior neurotrophic factor production or secretion promoting action.
  • neurotrophic factor for example, neurotrophin, TGF- ⁇ superfamily, neurokine family, growth factor and the like can be mentioned.
  • the neurotrophin is a general name of the nerve growth factor (NGF) gene family, and refers to a protein that plays an important role in differentiation and functional homeostasis of the cells of the central and peripheral nervous systems, formation of synapse, regeneration and repair of damage and the like.
  • NGF nerve growth factor
  • BDNF brain-derived neurotrophic factor
  • NT-3 neurotrophin-3
  • NT-4/5 neurotrophin-4/5
  • NT-6 neurotrophin-6
  • the neurotrophin preferably includes NGF, BDNF, NT-3 and the like.
  • the TGF- ⁇ superfamily means a protein group known to have a structure characterized by the position of cysteine in a mature molecule, and exhibit a great diversity of actions on various cells and tissues.
  • the TGF- ⁇ superfamily is preferably GDNF, GDF-15 and the like.
  • CNTF ciliary neurotrophic factor
  • IL-6 interleukin 6
  • IGF-1 insulin growth factor-1
  • basic fibroblast growth factor basic fibroblast growth factor
  • the neurotrophic factor is preferably neurotrophin, TGF- ⁇ superfamily and the like, more preferably NGF, BDNF, NT-3, GDNF, GDF-15 and the like.
  • the compound of the present invention has a motor nerve or sensory nerve conduction velocity improving action, pain (e.g., neuropathic pain) ameliorating action.
  • the compound of the present invention is useful as an agent for the prophylaxis or treatment of, for example, neurodegenerative diseases (e.g., Alzheimer's senile dementia, Parkinson's syndrome, Huntington's chorea, amyotrophic lateral sclerosis (ALS), Down's syndrome and the like); peripheral neuropathies (e.g., diabetic neuropathy, cancer treatment-induced neuropathy and the like); diabetic cardiac myopathy; peripheral nerve injury; spinal injury; multiple sclerosis; cerebral ischemic disease; epilepsy; depression; inflammatory bowel disease (e.g., inflammatory colitis and the like); chronic pain (e.g., cancer pain and the like); behavioral abnormalities accompanied by dementia (e.g., wandering, aggressive behavior and the like); anxiety disorder; numbness caused by wound; pain; autonomic abnormalities (e.g., diabetic autonomic disorder, asymptomatic hypoglycemia, gastroparesis, neuropathic diarrhea and constipation, erectile dysfunction, orthostatic hypotension
  • the compound of the present invention is also useful as an agent for the prophylaxis or treatment of diseases such as diabetes (e.g., type-1 diabetes, type-2 diabetes, gestational diabetes etc.), impaired glucose tolerance (IGT), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypo-HDL-emia, postprandial hyperlipidemia and the like), hyperinsulinemia, obesity, hyperphagia, hypertension, cardiovascular disease (e.g., atherosclerosis and the like) and the like; or a syndrome (e.g., syndrome X, visceral obesity syndrome and the like) comprising combination of some of these diseases.
  • diabetes e.g., type-1 diabetes, type-2 diabetes, gestational diabetes etc.
  • IIGT impaired glucose tolerance
  • hyperlipidemia e.g., hypertriglyceridemia, hypercholesterolemia, hypo-HDL-emia, postprandial hyperlipidemia and the like
  • hyperinsulinemia e.g., obesity, hyperphagia,
  • the compound of the present invention is used for secondary prophylaxis or suppression of progression (e.g., suppression of progression of impaired glucose tolerance into diabetes) of the above-mentioned various diseases (e.g., cardiac infarction and the like).
  • progression e.g., suppression of progression of impaired glucose tolerance into diabetes
  • various diseases e.g., cardiac infarction and the like.
  • the compound of the present invention is useful as an agent for ameliorating peripheral neuropathy or brain metabolic disorder; a promoter of curing skin injury caused by metabolic or endocrine system disease such as diabetes, and by wound; pancreatic regeneration agent (pancreatic function recovering agent); renal regeneration agent (renal function recovering agent); an agent for ameliorating or suppressing pain (e.g., neuropathic pain); prophylactic agent of amputation of lower limb; a prophylactic agent of sudden death and the like.
  • pancreatic regeneration agent pancreatic function recovering agent
  • renal regeneration agent renal function recovering agent
  • an agent for ameliorating or suppressing pain e.g., neuropathic pain
  • prophylactic agent of amputation of lower limb a prophylactic agent of sudden death and the like.
  • the dose of the compound of the present invention varies depending on the administration subject, administration route, target disease, condition and the like, it is, for example, in the case of oral administration to an adult patient with peripheral neuropathy (e.g., diabetic neuropathy), generally about 0.01–100 mg/kg body weight, preferably 0.05–30 mg/kg body weight, more preferably 0.1–2 mg/kg body weight, per dose, which amount is desirably administered once to 3 times a day.
  • peripheral neuropathy e.g., diabetic neuropathy
  • the compound of the present invention can be used in combination with a pharmaceutical agent (hereinafter to be abbreviated as a combination drug) such as a therapeutic agent of diabetes, a therapeutic agent of diabetic complications, an antihyperlipemic agent, a hypotensive agent, an antiobesity agent, a diuretic, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent, a therapeutic agent of osteoporosis, an antidementia agent, an agent for ameliorating erectile dysfunction, a therapeutic agent of incontinentia or pollakiuria, an antiepileptic agent, an antidepressant, an opioid agonist, a non-steroidal anti-inflammatory drug, a local anesthetic, vitamins and the like.
  • a pharmaceutical agent hereinafter to be abbreviated as a combination drug
  • a pharmaceutical agent such as a therapeutic agent of diabetes, a therapeutic agent of diabetic complications, an antihyperlipemic agent, a hypotensive agent, an anti
  • the time of administration of the compound of the present invention and a combination drug is not limited, and these may be administered to an administration subject simultaneously or in a staggered manner.
  • a concrete mode of administration for example, (1) administration of a single preparation obtained by simultaneous formulation of the compound of the present invention and a combination drug, (2) simultaneous administration of two kinds of preparations obtained by separate formulation of the compound of the present invention and a combination drug, by the same administration route, (3) time staggered administration of two kinds of preparations obtained by separate formulation of the compound of the present invention and a combination drug, by the same administration route, (4) simultaneous administration of two kinds of preparations obtained by separate formulation of the compound of the present invention and a combination.
  • the dose of the combination drug can be appropriately determined based on the dose clinically employed.
  • the mixing ratio of the compound of the present invention and a combination drug can be appropriately determined according to the administration subject, administration route, target disease, condition, combination and the like.
  • 0.01–100 parts by weight of a combination drug can be used relative to 1 part by weight of the compound of the present invention.
  • insulin preparations e.g. animal insulin preparations obtained by extraction from the bovine or swine pancreas; human insulin preparations synthesized by a genetic engineering technique using Escherichia coli or a yeast; insulin-zinc; protamine-insulin-zinc, a fragment or derivative of insulin (e.g., INS-1 etc.), insulin sensitizers (e.g.
  • pioglitazone hydrochloride pioglitazone hydrochloride, rosiglitazone (maleate), GI-262570, reglixane (JTT-501), netoglitazone (MCC-555), YM-440, KRP-297, CS-011, FK-614, the compounds described in WO99/58510 (e.g., (E)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid), ragaglitazar (NN-622), AR-H-039242, BMS-298585, EML-16336, tesaglitazar (AZ-242), balaglitazone (NN-2344), ONO-5816, BM-13-1258, LM-4156, MBX-102, LY-519818, MX-6054, LY-510929 etc.), ⁇ -glucosidase inhibitors (e.
  • aldose reductase inhibitors e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-112 and the like
  • neurotrophic factors and increasing drugs thereof e.g., NGF, NT-3, BDNF, neurotrophin production or secretion promoters described in WO01/14372 (e.g., 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole and the like) and the like
  • nerve regeneration enhancers e.g., Y-128 and the like
  • PKC inhibitors e.g., LY-333531 and the like
  • AGE inhibitors e.g., ALT946, pimagedine, pyratoxanthine, N-phenacylthiazolium bromide (ALT766),
  • statin compounds e.g., cerivastatin, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin and salts thereof (e.g., sodium salt) and the like
  • cholesterol synthesis inhibitors e.g., compounds described in WO97/10224, such as N-[[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl]-piperidine-4-acetic acid and the like
  • fibrate compounds e.g., bezafibrate, clofibrate, simfibrate, clinofibrate and the like
  • fibrate compounds e.g., bezafibrate, clofibrate, simfi
  • angiotensin converting enzyme inhibitors e.g., captopril, enalapril, delapril and the like
  • r angiotensin II antagonists e.g., candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, asosartan etc.
  • calcium antagonists e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine and the like
  • clonidine and the like can be mentioned.
  • antiobesity drugs acting on the central nervous system e.g. dexfenfluramine, fenfluramine, phentermine, sibutramine, anfepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex, and the like
  • pancreatic lipase inhibitors e.g., orlistat etc.
  • ⁇ 3 agonists e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc.
  • anorectic peptides e.g., leptin, CNTF (ciliary neurotrophic factor) etc.
  • cholecystokinin agonists e.g., lintitript, FPL-15849 etc.
  • xanthine derivatives e.g., sodium salicylate and theobromine, calcium salicylate and theobromine, and the like
  • thiazide preparations e.g., ethiazide, cyclopenthiazide., trichloromethyazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazide and the like
  • antialdosterone preparations e.g., spironolactone, triamterene and the like
  • carbonic anhydrase inhibitors e.g., acetazolamide and the like
  • chlorobenzenesulfonamide preparations e.g., chlortalidone, mefruside, indapamide and the like
  • azosemide isosorbide, etacrynic acid
  • chemotherapeutic agent for example, alkylation agents (e.g., cyclophosphamide, ifosfamide and the like), metabolic antagonists (e.g., methotrexate, 5-fluorouracil and the like), anti-cancer antibiotics (e.g., mitomycin, adriamycin and the like), plant-derived anti-cancer agents (e.g., vincristin, vindesine, taxol and the like), cisplatin, carboplatin, etopoxide and the like can be mentioned.
  • alkylation agents e.g., cyclophosphamide, ifosfamide and the like
  • metabolic antagonists e.g., methotrexate, 5-fluorouracil and the like
  • anti-cancer antibiotics e.g., mitomycin, adriamycin and the like
  • plant-derived anti-cancer agents e.g., vincristin, vindesine, taxo
  • immunotherapeutic agent for example, microorganism or bacterial components (e.g., a muramyl dipeptide derivative, picibanil and the like), polysaccharides having immunity potentiating activity (e.g., lentinan, sizofiran, krestin and the like), cytokines obtained by genetic engineering techniques (e.g., interferon, interleukin (IL) and the like), colony stimulating factors (e.g., granulocyte colony stimulating factor, erythropoietin and the like) and the like can be mentioned, with preference given to IL-1, IL-2, IL-12 and the like.
  • IL-1 interferon, interleukin (IL)
  • IL-12 granulocyte colony stimulating factor
  • heparin e.g., heparin sodium, heparin calcium, dalteparin sodium and the like
  • warfarin e.g., warfarin potassium and the like
  • anti-thrombin drugs e.g., aragatroban and the like
  • thrombolytic agents e.g., urokinase, tisokinase,reteplase, nateplase, monteplase, pamiteplase and the like
  • platelet aggregation inhibitors e.g., ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride and the like
  • the therapeutic agent of osteoporosis for example, alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, reminderonate disodium and the like can be mentioned.
  • antidementia agent for example, tacrine, donepezil, rivastigmine, galantamine and the like can be mentioned.
  • agent for ameliorating erectile dysfunction for example, apomorphine, sildenafil citrate and the like can be mentioned.
  • incontinentia or pollakiuria for example, flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like can be mentioned.
  • antiepileptic agent for example, gabapentin, carbamazepine and the like can be mentioned.
  • antidepressant for example, amitriptyline, imipramine and the like can be mentioned.
  • opioid agonist for example, morphine and the like can be mentioned.
  • non-steroidal anti-inflammatory drug for example, aspirin, acetaminophen, indomethacin and the like can be mentioned.
  • lidocaine for example, lidocaine, capsaicin and the like can be mentioned.
  • vitamins for example, vitamin B1, vitamin B12 and the like can be mentioned.
  • drugs having a cachexia-ameliorating action established in animal models or clinical situations such as cyclooxygenase inhibitors (e.g., indomethacin and the like) [ Cancer Research, Vol. 49, 5935–5939, 1989], progesterone derivatives (e.g., megesterol acetate) [ Journal of Clinical Oncology, Vol. 12, 213–225, 1994], glucosteroid (e.g., dexamethasone and the like), metoclopramide agents, tetrahydrocannabinol agents (ibid.), fat metabolism improving agents (e.g., eicosapentaenoic acid and the like) [ British Journal of Cancer, Vol.
  • cyclooxygenase inhibitors e.g., indomethacin and the like
  • progesterone derivatives e.g., megesterol acetate
  • glucosteroid e.g., dexamethasone and the like
  • growth hormones IGF-1, or antibodies to a cachexia-inducing factor such as TNF- ⁇ , LIF, IL-6, Oncostatin M and the like, can be also used in combination with the compound of the present invention.
  • the combination drug is preferably an insulin preparation, an insulin sensitizer, ⁇ -glucosidase inhibitor, a biguanide, an insulin secretagogue (preferably a sulfonylurea), an aldose reductase inhibitor, a PKC inhibitor, an antiepileptic agent, an antidepressant, an opioid agonist, a non-steroidal anti-inflammatory drug and the like.
  • combination drugs may be used in combination of two or more kinds at an appropriate ratio.
  • preferable combinations when two or more kinds of the combination drugs are used for example, the following can be mentioned.
  • the dose of the both components can be reduced within a safe range in consideration of the opposing effect of the components.
  • a combination drug such as an insulin sensitizer, an insulin secretagogue (preferably a sulfonylurea) and a biguanide can be reduced from the normal dose. Therefore, the opposing effect caused by these agents can be safely prevented.
  • the doses of a therapeutic agent of diabetic complications, an antihyperlipemic agent and a hypotensive agent can be reduced, and as a result, the side effects that would be caused by these agents can be prevented effectively.
  • the compound (I) can be produced by, for example, the following Methods A–G, or a method analogous thereto.
  • compound (II) is subjected to an amidation reaction to produce compound (I).
  • This reaction is carried out according to a method known per se, such as a method for directly condensing compound (II) with compound (III) using a condensation agent, a method for appropriately reacting a reactive derivative of compound (II) with compound (III) and the like.
  • condensation agent one such as carbodiimide type condensation reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide or its hydrochloride and the like; phosphoric acid type condensation reagents such as diethyl cyanophosphate, diphenylphosphoryl azide and the like; carbonyl diimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate and the like can be mentioned.
  • carbodiimide type condensation reagents such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-dimethylaminopropylcarbodiimide or its hydrochloride and the like
  • phosphoric acid type condensation reagents such as diethyl cyanophosphate, diphenylphosphoryl azide and the like
  • amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; ethyl acetate, water and the like can be mentioned. Two or more kinds of these solvents may be used in a mixture at appropriate ratios.
  • the amount of compound (III) to be used is generally 0.1–10 molar equivalents, preferably 0.3–3 molar equivalents, relative to compound (II).
  • the amount of the condensation agent to be used is generally 0.1–10 molar equivalents, preferably 0.3–3 molar equivalents, relative to compound (II).
  • the reaction efficiency can be improved by the use of a suitable condensation promoter (e.g., 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide and the like) where necessary.
  • a suitable condensation promoter e.g., 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide and the like
  • the reaction efficiency can be improved by generally adding an organic amine type base such as triethylamine and the like.
  • the amount of the above-mentioned condensation promoter and the organic amine type base to be used is generally 0.1–10 molar equivalents, preferably 0.3–3 molar equivalents, relative to compound (II).
  • the reaction temperature is generally ⁇ 30° C. to 100° C.
  • the reaction time is generally 0.5–60 hrs.
  • a reactive derivative of compound (II) for example, acid anhydride, acid halide (acid chloride, acid bromide), imidazolide, or mixed acid anhydride (e.g., anhydride with methyl carbonate, ethyl carbonate or isobutyl carbonate, and the like) and the like can be mentioned.
  • the reaction is generally carried out in the presence of a base, in a solvent that does not exert an influence on the reaction.
  • amines such as triethylamine, pyridine, N-methylmorpholine, N,N-dimethylaniline, 4-dimethylaminopyridine and the like
  • alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like can be mentioned.
  • the amount of the base to be used is generally 0.1–10 molar equivalents, preferably 0.3–3 molar equivalents, relative to compound (II).
  • amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; ethyl acetate, water and the like can be mentioned. Two or more kinds of these solvents may be used in a mixture at appropriate ratios.
  • the reaction can be also carried out in the absence of a base.
  • the amount of compound (III) to be used is generally 0.1–10 molar equivalents, preferably 0.3–3 molar equivalents, relative to compound (II).
  • the reaction temperature is generally ⁇ 30° C. to 100° C.
  • the reaction time is generally 0.5–20 hrs.
  • compound (II) is reacted with chlorocarbonic acid esters (e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate and the like) in the presence of a base and then reacted with compound (III).
  • chlorocarbonic acid esters e.g., methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate and the like
  • amines such as triethylamine, aniline, N-methylmorpholine, N,N-dimethylaniline, 4-dimethylaminopyridine and the like
  • alkali metal salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like can be mentioned.
  • the amount of the base to be used is generally 0.1–10 molar equivalents, preferably 0.3–3 molar equivalents, relative to compound (II).
  • the amount of the compound (III) to be used is generally 0.1–10 molar equivalents, preferably 0.3–3 molar equivalents, relative to compound (II).
  • the reaction temperature is generally ⁇ 30° C. to 100° C.
  • the reaction time is generally 0.5–20 hrs.
  • the compound (I) thus obtained can be isolated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • the compound (II) to be used as a starting compound in the above-mentioned Method A can be produced by a method described in, for example, WO97/36882, WO01/14372 and the like, or a method analogous thereto.
  • compound (III) can be produced by a method known per se.
  • L is a leaving group, and other symbols are as defined above.
  • a halogen atom e.g., fluorine, chlorine, bromine, iodine
  • an oxygen functional group such as alkoxy group, phenoxy group and the like
  • a sulfur functional group such as sulfanyl group, sulfinyl group, sulfonyl group and the like
  • an amino group an acyl group and the like
  • compound (Ia) is reacted with compound (IV) to give compound (I).
  • This reaction is carried out according to a conventional method generally in the presence of a base in a solvent that does not exert an adverse influence on the reaction.
  • alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like
  • alkaline earth metal salts such as barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like
  • amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and the like
  • metal hydrides such as potassium hydride, sodium hydride and the like
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; and the like can be mentioned.
  • the amount of the base to be used is preferably about 1–about 5 molar equivalents., relative to compound (Ia).
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; ketones such as acetone, 2-butanone and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like, water and the like can be mentioned.
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like
  • ethers such as tetrahydrofuran, dioxane, diethyl ether and the like
  • ketones such as acetone, 2-butanone and the like
  • halogenated hydrocarbons such as chloroform, dichloromethane and the like
  • amides such as N,N-dimethylformamide and the like
  • the reaction temperature is generally about ⁇ 50° C. to about 150° C., preferably about ⁇ 10° C. to about 100° C.
  • the reaction time is generally about 0.5–about 20 hrs.
  • the compound (I) thus obtained can be isolated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • the compound (Ia) to be used as a starting compound in the above-mentioned Method B can be produced according to the aforementioned Method A.
  • compound (IV) can be produced by a method known per se.
  • the compound (Ib) having an optionally substituted aryl group for R 1 in the formula (I) can be also produced by the following Method C.
  • La is a halogen atom
  • R 1a is an optionally substituted aryl
  • other symbols are as defined above.
  • halogen atom for La fluorine, chlorine, bromine and iodine can be mentioned.
  • aryl group for R a
  • one from those exemplified for the “optionally substituted hydrocarbon group” for R 1 , wherein the “hydrocarbon group” is an aryl group can be mentioned.
  • phenyl optionally substituted by 1 or 2 substituent(s) selected from C 1-6 alkyl and halogen atom, and the like are preferable.
  • compound (V) examples include phenylboronic acid, tolylboronic acid, 4-fluorophenylboronic acid and the like.
  • compound (Iaa) and compound (V) are reacted in the presence of a suitable base as necessary and using a palladium catalyst to give compound (Ib).
  • This reaction is performed according to a conventional method generally in the presence of a base in a solvent that does not exert an adverse influence on the reaction.
  • alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like
  • alkaline earth metal salts such as barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like
  • amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and
  • metal hydrides such as potassium hydride, sodium hydride and the like
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t.-butoxide and the like; and the like can be mentioned.
  • the amount of the base to be used is preferably about 1–about 5 molar equivalents, relative to compound (Iaa).
  • the amount of compound (V) to be used is preferably about 1–about 5 molar equivalents, relative to compound (Iaa).
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; ketones such as acetone, 2-butanone and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like, water and the like can be mentioned.
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like
  • ethers such as tetrahydrofuran, dioxane, diethyl ether and the like
  • ketones such as acetone, 2-butanone and the like
  • halogenated hydrocarbons such as chloroform, dichloromethane and the like
  • amides such as N,N-dimethylformamide and the like
  • the reaction temperature is generally about ⁇ 50° C. to about 150° C., preferably about ⁇ 10° C. to about 100° C.
  • the reaction time is generally about 0.5–about 20 hrs.
  • the compound (Ib) thus obtained can be isolated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • the compound (Iaa) to be used as a starting compound in the above-mentioned Method C can be produced by, for example, the aforementioned Method A.
  • compound (V) can be produced by a method known per se.
  • X 1 is an oxygen atom or a sulfur atom
  • R 2a is a hydrogen atom or an optionally substituted alkyl group
  • R 2b is an optionally substituted alkyl group or an optionally substituted aryl group, and other symbols are as defined above.
  • R 2a or R 2b one from those exemplified for the “optionally substituted hydrocarbon group” for R 1 , wherein the “hydrocarbon group” is an alkyl group, can be mentioned. Particularly, C 1-6 alkyl and the like are preferable.
  • compound (VI) examples include, phenyl isocyanate, isopropyl isocyanate, phenylthio isocyanate and the like.
  • This reaction is performed according to a conventional method generally under neutral conditions and where necessary, in the presence of a suitable base in a solvent that does not exert an adverse influence on the reaction.
  • alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like
  • alkaline earth metal salts such as barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like
  • amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and
  • metal hydrides such as potassium hydride, sodium hydride and the like
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like and the like can be mentioned.
  • the amount of the base to be used is preferably about 1–about 5 molar equivalents, relative to compound (Ic).
  • the amount of compound (VI) to be used is preferably about 1–about 5 molar equivalents, relative to compound (Ic).
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether and the like; ketones such as acetone, 2-butanone and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; amides such as N,N-dimethylformamide and the like; sulfoxides such as dimethyl sulfoxide and the like and the like can be mentioned.
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like
  • ethers such as tetrahydrofuran, dioxane, diethyl ether and the like
  • ketones such as acetone, 2-butanone and the like
  • halogenated hydrocarbons such as chloroform, dichloromethane and the like
  • amides such as N,N-dimethylformamide and the like
  • the reaction temperature is generally about ⁇ 50° C. to about 150° C., preferably about ⁇ 10° C. to about 100° C.
  • the reaction time is generally about 0.5–about 20 hrs.
  • the compound (Id) thus obtained can be isolated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • the compound (Ic) to be used as a starting compound in the above-mentioned Method D can be produced by, for example, the aforementioned Method A or Method B.
  • compound (VI) can be produced by a method known per se.
  • R 2c and R 2d are the same or different and each is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted aryl group, R 6 is a C 1-6 alkyl group, and other symbols are as defined above.
  • This reaction is performed according to a conventional method generally under neutral conditions and where necessary, in the presence of a suitable base, in a solvent that does not exert an adverse influence on the reaction.
  • alkali metal salts such as lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like
  • alkaline earth metal salts such as barium carbonate, calcium carbonate, barium hydroxide, calcium hydroxide and the like
  • amines such as pyridine, triethylamine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene and
  • metal hydrides such as potassium hydride, sodium hydride and the like
  • alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like; and the like can be mentioned.
  • the amount of the base to be used is preferably about 1–about 5 molar equivalents, relative to compound (Ie).
  • the amount of compound (VII) to be used is preferably about 1–about 5 molar equivalents, relative to compound (Ie).
  • aromatic hydrocarbons such as benzene, toluene, xylene and the like
  • ethers such as tetrahydrofuran, dioxane, diethyl ether and the like
  • ketones such as acetone, 2-butanone and the like
  • halogenated hydrocarbons such as chloroform, dichloromethane and the like
  • amides such as N,N-dimethylformamide and the like
  • sulfoxides such as dimethyl sulfoxide and the like, water and the like
  • solvents may be used in a mixture at appropriate ratios.
  • the reaction temperature is generally about ⁇ 50° C. to about 150° C., preferably about ⁇ 10° C. to about 100° C.
  • the reaction time is generally about 0.5–about 20 hrs.
  • the compound (If) thus obtained can be isolated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • the compound (Ie) to be used as a starting compound in the above-mentioned Method E can be produced by, for example, the aforementioned Method A or Method B.
  • compound (VII) can be produced by a method known per se.
  • This method can be performed in the same manner as in the aforementioned Method A.
  • the compound (Ig) thus obtained can be isolated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • the compound (Ic) to be used as a starting compound in the above-mentioned Method F can be produced by, for example, the aforementioned Method A or Method B.
  • compound (VIII) can be produced by a method known per se.
  • compound (Ia) used as a starting compound in the aforementioned Method B compound (Iaa) wherein the leaving group for L is a halogen atom, and compound (Iaa) to be used as a starting compound in Method C can be produced by, for example, the following Method G.
  • This reaction is performed according to, for example, a known Sandmeyer reaction.
  • compound (Ie) is subjected to diazotization reaction, the obtained diazonium salt and a monovalent or divalent copper salt and hydrochloric acid or hydrobromic acid are reacted in a solvent that does not exert an adverse influence on the reaction to give compound (Iaa).
  • the diazotization reaction is carried out using a diazotization reagent according to a known method.
  • a diazotization reagent for example, nitrous acid, nitrites such as sodium nitrite and the like; nitrosyl halides such as nitrosyl chloride and the like; and the like are used.
  • the amount of the diazotization reagent to be used is generally about 1–about 5 molar equivalents, relative to compound (Ie).
  • copper(I) chloride, copper(I) bromide, copper(I) iodide, copper(II) chloride, copper(II) bromide, copper(II) iodide and the like can be mentioned.
  • the amount of the copper salt to be used is generally about 1–5 molar equivalents, relative to compound (Ie).
  • solvents such as methanol, ethanol and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic amines such as quinoline, pyridine and the like; acetone, dimethyl sulfoxide, phosphoric acid, acetic acid, water and the like can be mentioned.
  • alcohols such as methanol, ethanol and the like
  • ethers such as tetrahydrofuran, dioxane and the like
  • aromatic amines such as quinoline, pyridine and the like
  • acetone, dimethyl sulfoxide, phosphoric acid, acetic acid, water and the like can be mentioned.
  • the reaction temperature is generally about ⁇ 20° C. to 200° C., preferably about 0° C. to 150° C.
  • the reaction time is generally about 0.5–about 20 hrs.
  • This reaction can be also carried out by reacting compound (Ie) with alkyl nitrite in the presence of a monovalent or divalent copper salt in a solvent that does not exert an influence on the reaction.
  • the amount of copper salt to be used is generally about 1–5 molar equivalents, relative to compound (Ie).
  • ethers such as tetrahydrofuran, dioxane and the like; acetonitrile, acetone, dimethyl sulfoxide and the like can be mentioned. These solvents may be used in a mixture at appropriate ratios.
  • alkyl nitrite for example, t-butyl nitrite, isoamyl nitrite and the like can be mentioned.
  • the amount of alkyl nitrite to be used is generally about 1–5 molar equivalents, relative to compound (Ie).
  • the reaction temperature is generally about ⁇ 20° C. to 200° C., preferably about 0° C. to 150° C.
  • the reaction time is generally about 0.5–about 20 hrs.
  • the compound (Iaa) thus obtained can be isolated and purified by a known separation and purification means, such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • a known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, a method using an ion exchange resin and a scavenger resin and the like.
  • these groups may have a protecting group introduced therein, such as one generally used in peptide chemistry and the like.
  • the objective compound can be obtained by removing the protecting group as necessary after the reaction.
  • amino-protecting group for example, formyl, C 1-6 alkyl-carbonyl (e.g., acetyl, propionyl and the like), C 1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like), benzoyl, C 7-13 aralkyl-carbonyl (e.g., benzylcarbonyl and the like), C 7-13 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl and the like), trityl, phthaloyl, N,N-dimethylaminomethylene, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like
  • halogen atom(s) e.g., fluorine, chlorine, bromine, iodine and the like
  • C 1-6 alkoxy e.g., methoxy, ethoxy, propoxy and the like
  • nitro and the like e.g., benzyl alcohol
  • C 1-6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like
  • C 7-13 aralkyl e.g., benzyl and the like
  • phenyl, trityl silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like)
  • C 2-6 alkenyl e.g., 1-allyl and the like
  • halogen atom(s) e.g., fluorine, chlorine, bromine, iodine and the like
  • C 1-6 alkoxy e.g., methoxy, ethoxy, propoxy and the like
  • nitro and the like e.g., benzyl alcohol
  • C 1-6 alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like
  • phenyl, trityl C 7-13 aralkyl (e.g., benzyl and the like), formyl, C 1-6 alkyl-carbonyl (e.g., acetyl, propionyl and the like), benzoyl, C 7-13 aralkyl-carbonyl (e.g., benzylcarbonyl and the like), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl and the like), C 2-6 alkenyl (e.g., trimethylsilyl, trieth
  • halogen atom(s) e.g., fluorine, chlorine, bromine, iodine and the like
  • C 1-6 alkyl e.g., methyl, ethyl, propyl and the like
  • C 1-6 alkoxy e.g., methoxy, ethoxy, propoxy and the like
  • carbonyl-protecting group for example, cyclic acetal (e.g., 1,3-dioxane and the like), non-cyclic acetal (e.g., di-C 1-6 alkyl acetal and the like) and the like can be mentioned.
  • cyclic acetal e.g., 1,3-dioxane and the like
  • non-cyclic acetal e.g., di-C 1-6 alkyl acetal and the like
  • the removing method of these protecting groups may be carried out by methods known per se, for example, the methods described in Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1980, and the like.
  • employed are the methods using acids, bases, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide, etc.), etc.; and reduction method, and the like.
  • the compound When the starting compound can form a salt in each of the aforementioned reactions, the compound may be used in the form of a salt.
  • a salt for example, those exemplified for the salt of the compound represented by the formula (I) can be used.
  • the compound (I) includes optical isomers, stereoisomers, regioisomers and rotational isomers, those are also encompassed in the compound (I), and can be obtained as a single compound by synthetic methods and separation methods known per se.
  • optical isomers of the compound (I) exist, optical isomers resolved from the compound are also encompassed in the compound (I).
  • optical isomers can be produced by a method known per se. Concretely, an optically active isomer can be obtained using an optically active synthetic intermediate or by optical resolution of a final racemate by a conventional method.
  • a method known per se such as a fractional recrystallization method, a chiral column method, a diastereomer method, and the like can be used.
  • the method which comprises allowing a racemate and an optically-active compound (e.g., (+)-mandelic acid, ( ⁇ )-andelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, cinchonine, ( ⁇ )-cinchonidine, brucine, etc.) to form a salt, which is then separated through fractional recrystallization method, followed by, when desired, subjecting the salt to a neutralization step to give a free optical isomer.
  • an optically-active compound e.g., (+)-mandelic acid, ( ⁇ )-andelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, ( ⁇ )-1-phenethylamine, cinchonine, ( ⁇ )-cinchonidine, brucine, etc.
  • the method of separating by applying a racemate or a salt thereof, to a column for fractionating optical isomers chiral column.
  • the optical isomers are separated by applying a mixture of optical isomers to a chiral column, such as ENANTIO-OVM (manufactured by Tosoh Corp.), CHIRAL SERIES (manufactured by Daicel Co.), etc., and developing with water, various buffers (e.g., phosphate buffer) and organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.), singly or as a suitable mixture of them.
  • a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Science Co.), etc. is used for separation.
  • a racemic mixture is chemically reacted with an optically-active reagent to give a mixture of diastereomers, which is subjected to an ordinary separation means (e.g., fractional recrystallization, chromatography, etc.) to give a single compound, which is then subjected to a chemical treatment (e.g., hydrolysis reaction etc.) to separate the optically-active reagent site from the compound to give an optical isomer.
  • an ordinary separation means e.g., fractional recrystallization, chromatography, etc.
  • a chemical treatment e.g., hydrolysis reaction etc.
  • compound (I) has a hydroxy or a primary or secondary amino in the molecule
  • the compound and an optically-active organic acid e.g., MTPA [ ⁇ -methoxy- ⁇ -(trifluoromethyl)phenyl-acetic acid], ( ⁇ )-menthoxyacetic acid, etc.
  • condensation reaction to give the respectively corresponding ester or amide diastereomer
  • compound (I) has a carboxylic acid group
  • the compound and an optically-active amine or alcohol reagent are subjected to condensation reaction to give an amide or ester diastereomer.
  • the separated diastereomer is then subjected to acidic or basic hydrolysis reaction, through which it is converted into the optical isomer of the original compound.
  • % means percent by weight unless specifically indicated.
  • room temperature means a temperature of 1–30° C.
  • Methyl 3-[4-(4-chlorophenyl)-2-phenyl-5-oxazolyl]propionate (1.50 g, 88%) was obtained as a yellow oil from a fraction eluted with hexane-ethyl acetate (6:1, volume ratio).
  • the reaction mixture was concentrated and poured into 10% aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in acetic acid (50 mL) and zinc powder (10 g) was added. The mixture was stirred with heating under reflux for 30 min. Insoluble material was removed by filtration, and the filtrate was concentrated and poured into 10% aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated.
  • tert-Butyl 2-(ethylsulfanyl)ethylcarbamate was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). (1.83 g, yield 100%).
  • reaction mixture was diluted with water, acidified with 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate.
  • the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-[2-(4-tert-butylphenoxy)-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (1.6 g, yield 80%) as crystals. Recrystallization from ethanol gave colorless prism crystals. melting point: 166–167° C.
  • the residue was diluted with ethanol (15 mL) and a 2N aqueous sodium hydroxide solution (10 mL) was added at 0° C., and the mixture was further stirred for 1.5 hrs.
  • Water was added to the reaction mixture, and the mixture was washed with diethyl ether.
  • the aqueous layer was acidified with 2N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed successively with water and saturated brine (100 mL), dried over anhydrous magnesium sulfate and concentrated.
  • the residue was dissolved in pyridine (30 mL) and the mixture was stirred with heating under reflux for 4 hrs.
  • reaction mixture was concentrated, dissolved in ethanol (15 mL) and 2N aqueous sodium hydroxide solution (15 mL) was added. The mixture was further stirred for 1 hr. Water was added to the reaction mixture, and the mixture was washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate.
  • the residue was washed with diethyl ether.
  • the aqueous layer was acidified with 2N aqueous hydrochloric acid solution and extracted with diethyl ether.
  • the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated.
  • the residue was dissolved in 10% hydrochloric acid methanol solution (30 mL) and the mixture was stirred with heating under reflux for 1.5 hrs.
  • the reaction mixture was concentrated and saturated aqueous sodium hydrogen carbonate was added.
  • the mixture was extracted with diethyl ether.
  • the organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated.
  • the residue was subjected to silica gel column chromatography, and an oil was obtained from a fraction eluted with diethyl ether-hexane (3:7, volume ratio).
  • the reaction mixture was poured into water, and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was dissolved in ethanol (10 mL) and a 2N aqueous sodium hydroxide solution (15 mL) was added. The mixture was further stirred for 1 hr. Water was added to the reaction mixture, and the mixture was washed with diethyl ether. The aqueous layer was acidified with 2N aqueous hydrochloric acid solution and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated.
  • Ethyl 5-(4-chlorophenyl)-5-oxopentanoate (30 g) was dissolved in diethyl ether (300 ml) and bromine (6.55 g) was added dropwise at room temperature.
  • An aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was neutralized with aqueous sodium hydrogen carbonate solution.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated.
  • the residue was dissolved in ethanol (200 mL) and thiourea (8.85 g) and sodium acetate (14.3 g) were added. The mixture was stirred with heating under reflux for 2 hrs.
  • This compound (30 g) was dissolved in a mixed solvent of tetrahydrofuran (300 ml)-ethanol (150 ml) and 2N aqueous sodium hydroxide solution was added at 0° C. The mixture was stirred at 60° C. for 1 hr. The reaction mixture was poured into water and 1N hydrochloric acid was added. The precipitated solid was collected by filtration to give 3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl]propionic acid (25.9 g, 94%) as a yellow powder. Recrystallization from ethanol gave yellow prism crystals. melting point: 116–118° C.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040142988A1 (en) * 2001-06-26 2004-07-22 Yasuo Sugiyama Tgf-beta superfamily production/secretion promoter
US20080070905A1 (en) * 2006-08-16 2008-03-20 J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US20100280023A1 (en) * 2005-06-23 2010-11-04 Kyowa Hakko Kogyo Co., Ltd. Thiazole derivatives
US8071631B2 (en) 2006-08-16 2011-12-06 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Small molecule inhibitors of kynurenine-3-monooxygenase

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1425505A (en) 1972-02-25 1976-02-18 Istituto Luco Farmaco Ditalia 5-substituted 2-amino-4-arylthiazoles and their preparation
JPS5283747A (en) 1976-01-01 1977-07-12 Yamanouchi Pharmaceut Co Ltd Novel nitrosourea derivatives
EP0526877A2 (en) 1991-08-06 1993-02-10 Bristol-Myers Squibb Company Peptide aldehydes as antithrombotic agents
EP0630894A1 (en) 1993-06-24 1994-12-28 Eisai Co., Ltd. Propenoic acid derivatives as adenosine A1 antagonists
JPH07101458A (ja) 1993-10-01 1995-04-18 Hiroshi Yoshihara 蓋の開放機構、一体成形ケースの蓋の開放機構、ワンプッシュ開放式ケース、一体成形ケースの製造方法及びワンプッシュ開放式ケースの製造方法
WO1997036882A1 (en) 1996-04-03 1997-10-09 Takeda Chemical Industries, Ltd. Oxazole derivatives, their production and use
WO1999002505A1 (en) 1997-07-10 1999-01-21 Janssen Pharmaceutica N.V. Il-5 inhibiting 6-azauracil derivatives
WO2000001679A1 (fr) 1998-07-01 2000-01-13 Takeda Chemical Industries, Ltd. Regulateurs du recepteur associe aux retinoides
EP0987265A1 (en) 1998-09-18 2000-03-22 Janssen Pharmaceutica N.V. Interleukin-5 inhibiting 6-azauracil derivatives
WO2001010866A1 (en) 1999-08-06 2001-02-15 Janssen Pharmaceutica N.V. Interleukin-5 inhibiting 6-azauracil derivatives
WO2001014372A2 (en) 1999-08-25 2001-03-01 Takeda Chemical Industries, Ltd. Oxazole and thiazole derivatives as neurotrophin production/secretion promoting agent
WO2001077101A1 (en) 2000-04-08 2001-10-18 Astrazeneca Ab Chemical compounds
WO2002020484A1 (en) 2000-09-04 2002-03-14 Astrazeneca Ab Chemical compounds
US20020103185A1 (en) * 2000-08-31 2002-08-01 Sanner Mark A. Pyrazole derivatives
WO2003000257A1 (fr) 2001-06-26 2003-01-03 Takeda Chemical Industries, Ltd. Promoteur de production/secretion de la superfamille des tgf-$g(b)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4614458B1 (ja) * 1967-04-07 1971-04-17

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1425505A (en) 1972-02-25 1976-02-18 Istituto Luco Farmaco Ditalia 5-substituted 2-amino-4-arylthiazoles and their preparation
JPS5283747A (en) 1976-01-01 1977-07-12 Yamanouchi Pharmaceut Co Ltd Novel nitrosourea derivatives
EP0526877A2 (en) 1991-08-06 1993-02-10 Bristol-Myers Squibb Company Peptide aldehydes as antithrombotic agents
EP0630894A1 (en) 1993-06-24 1994-12-28 Eisai Co., Ltd. Propenoic acid derivatives as adenosine A1 antagonists
JPH07101458A (ja) 1993-10-01 1995-04-18 Hiroshi Yoshihara 蓋の開放機構、一体成形ケースの蓋の開放機構、ワンプッシュ開放式ケース、一体成形ケースの製造方法及びワンプッシュ開放式ケースの製造方法
WO1997036882A1 (en) 1996-04-03 1997-10-09 Takeda Chemical Industries, Ltd. Oxazole derivatives, their production and use
WO1999002505A1 (en) 1997-07-10 1999-01-21 Janssen Pharmaceutica N.V. Il-5 inhibiting 6-azauracil derivatives
WO2000001679A1 (fr) 1998-07-01 2000-01-13 Takeda Chemical Industries, Ltd. Regulateurs du recepteur associe aux retinoides
EP0987265A1 (en) 1998-09-18 2000-03-22 Janssen Pharmaceutica N.V. Interleukin-5 inhibiting 6-azauracil derivatives
WO2001010866A1 (en) 1999-08-06 2001-02-15 Janssen Pharmaceutica N.V. Interleukin-5 inhibiting 6-azauracil derivatives
WO2001014372A2 (en) 1999-08-25 2001-03-01 Takeda Chemical Industries, Ltd. Oxazole and thiazole derivatives as neurotrophin production/secretion promoting agent
WO2001077101A1 (en) 2000-04-08 2001-10-18 Astrazeneca Ab Chemical compounds
US20020103185A1 (en) * 2000-08-31 2002-08-01 Sanner Mark A. Pyrazole derivatives
WO2002020484A1 (en) 2000-09-04 2002-03-14 Astrazeneca Ab Chemical compounds
WO2003000257A1 (fr) 2001-06-26 2003-01-03 Takeda Chemical Industries, Ltd. Promoteur de production/secretion de la superfamille des tgf-$g(b)

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
S. Bengtsson, et al., "Compounds Related to Clomethiazole-VI. Synthesis of Some Reference Compounds in Connection with Biotransformation Studies", Acta Pharm. Suec., (1982, pp. 37-42, vol. 19, No. 1.
Saito et al. Analytical Sciences 1994, 10(4), 679-81. *CAS Abstract attached. *
Saito et al. Journal of Chromatography, B: Biomedical Applications 1995, 674(2), 167-75. *CAS Abstract attached. *
T. Jakobiec, et al., "Synthesis of Derivatives of 2-Amino-4-P-Chlorophenylthiazole-5-Acetic Acid", Archivum Immunologiae et Thereapiae Experimentalis, (1978), pp. 935-941, vol. 26.
Ushijima et al. Analytical Science & Technology 1995, 8(4), 545-51. *CAS Abstract attached. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040142988A1 (en) * 2001-06-26 2004-07-22 Yasuo Sugiyama Tgf-beta superfamily production/secretion promoter
US7498352B2 (en) * 2001-06-26 2009-03-03 Takeda Pharmaceutical Company Limited TGF-β superfamily production/secretion promoter
US20100280023A1 (en) * 2005-06-23 2010-11-04 Kyowa Hakko Kogyo Co., Ltd. Thiazole derivatives
US20080070905A1 (en) * 2006-08-16 2008-03-20 J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US7994338B2 (en) * 2006-08-16 2011-08-09 The J. David Gladstone Institutes Small molecule inhibitors of kynurenine-3-monooxygenase
US8071631B2 (en) 2006-08-16 2011-12-06 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Small molecule inhibitors of kynurenine-3-monooxygenase
US8466182B2 (en) 2006-08-16 2013-06-18 The J. David Gladstone Institutes, A Testamentary Trust Established Under The Will Of J. David Gladstone Small molecule inhibitors of kynurenine-3-monooxygenase
US8710237B2 (en) 2006-08-16 2014-04-29 The J. David Gladstone Institute Small molecule inhibitors of kynurenine-3-monooxygenase

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